ABSTRACT The CHIPTS Combination Prevention (CP) Core promotes development and evaluation of interventions that integrate evidence-based behavioral, biomedical, technological and structural components to reduce HIV incidence and to optimize each step of the HIV care and prevention continua. In response to strategic planning and anticipation of the medicalization of HIV prevention, the CP Core focuses its resources on guiding efforts that address persistent gaps in access and adherence to care and prevention in key populations, including men who have sex with men of color, African American women, transgender individuals, youth, homeless, and incarcerated individuals. Within these key populations, we further target those with comorbidities of substance use and mental health disorders and other factors that interfere with access and adherence to antiretroviral therapy (ART). While efforts to produce measurable outcomes (e.g., viral suppression, reduction in incidence) to HIV prevention have shown remarkable success using ART, the research was conducted on populations compliant with medications. Yet the disorganizing effects in key populations of comorbid substance use and mental health disorders contribute to ?leaks? in the HIV prevention and care continua. Its three specific aims are: (1) SCIENCE: To lead the science agenda on combining behavioral, biomedical, technological and structural interventions to optimize HIV care and HIV prevention outcomes, with a focus on those with mental health and/or substance use disorders, domestically and globally; to lead in scientific research networks (e.g., HPTN, ACTG); (2) NETWORKING: To convene activities that present best practices for dissemination and scale-up of behavioral, biomedical, technological, and structural interventions; to promote science development by engaging investigators and community stakeholders; (3) CAPACITY BUILDING: To build capacity within affected communities, key stakeholders, and service organizations through community education and workforce training; to mentor emerging scientists and faculty on combination prevention approaches; to facilitate linkages between community members interested in HIV therapeutic or prevention research with ongoing research opportunities. This coordinated agenda of science, networking and capacity building will generate vanguard information and expertise that will guide efforts towards HIV eradication in both the general population and in key populations. The CP Core team is led by Director Cathy Reback, PhD, Co-Director Raphael Landovitz MD, MSc, and Associate Director Danielle Harris, MPH. Core services include: advise on research on combination HIV prevention; provide guidance on study of substance use and mental health in the context of HIV prevention; provide peer review; translate domestic HIV prevention strategies for use in foreign settings and back; advise and train cultural competence, especially in key populations with comorbid conditions; conduct workforce training; mentor emerging academicians.